Advancing Bladder Cancer Care by Imaging and Intravesical Immune Checkpoint Blockade

通过影像学和膀胱内免疫检查点阻断推进膀胱癌治疗

• 批准号: 10435605
• 负责人: Pradeep Tyagi
• 金额: $ 20.95万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-15 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10435605
• 关键词: Adverse effects; Anesthesia procedures; Antibodies; Antitumor Response; BCG Live; Bacillus Calmette-Guerin Therapy; Bladder; Bladder Neoplasm; Blood Substitutes; Caliber; Cancer Patient; Carcinogens; Carcinoma in Situ; Catheters; Cells; Cessation of life; Common Neoplasm; Cystectomy; Cystoscopy; Diarrhea; Diffusion; Dimethyl Sulfoxide; Drug Delivery Systems; Dyes; Early Diagnosis; Early identification; Emulsions; Epidermal Growth Factor Receptor; Exhibits; Experimental Designs; FGFR3 gene; Harvest; Healthcare Systems; Histopathology; Hyperplasia; Image; Image Enhancement; Imaging Techniques; Immune; Immune checkpoint inhibitor; Immunocompetent; Immunohistochemistry; Immunologic Surveillance; Immunotherapeutic agent; Immunotherapy; Infiltration; Injectable; Isoflurane; Length of Stay; Ligands; Liposomes; Magnetic Resonance Imaging; Magnetism; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Maps; Measures; Mediating; Monitor; Mus; Muscle; Nitrosamines; Nivolumab; Operating Rooms; PTGS2 gene; Patients; Pattern; Permeability; Pharmaceutical Preparations; Probability; Proteins; Randomized; Recurrence; Relaxation; Resistance; Resolution; Route; Salvage Therapy; Secondary to; Self Tolerance; Spleen; Stains; Steroids; Survival Analysis; T-Lymphocyte; Testing; Thinness; Time; Toxic effect; Transitional Cell Carcinoma; Tumor Cell Invasion; Tumor Volume; Tumor-Associated Vasculature; Tumor-infiltrating immune cells; Urethra; Urologic Neoplasms; Urothelium; Visualization; Water; Weight; angiogenesis; base; cancer care; cancer imaging; carcinogenesis; chemotherapy; contrast enhanced; contrast imaging; cost; dalton; feeding; gadobutrol; high risk; imaging approach; imaging modality; immune checkpoint blockade; improved; inhibitor; intravesical; minimally invasive; molecular size; novel; overexpression; programmed cell death protein 1; receptor; response; risk stratification; small molecule; soft tissue; treatment effect; tumor; tumor progression; uptake; virtual; virtual monitoring

This revised proposal leverages the preliminary findings of NCT04369560 to develop intravesical imaging and immunotherapy approach for bladder cancer (BCa). While cystoscopy can detect exophytic tumors (≥2mm in diameter), the poor soft tissue resolution of the available imaging modalities renders them inadequate to detect tumor invasion, carcinoma-in-situ (CIS) and the tumor vasculature associated with aggressive cancer. This critical gap in tumor visualization adversely impacts the early identification of high risk BCa patients and patients most likely to benefit from chemotherapy and/or immunotherapy. Although intravesical immunotherapy of Bacillus Calmette–Guérin (BCG) halts BCa progression and muscle invasion, still 40% of patients exhibit BCG-resistant tumor with the expression of: programmed death (PD)L1, PDL2 ligands for engaging with PD1 receptor on T cells to suppress the anti-tumor response. While the anti-tumor response is inhibited by injectable antibodies, adverse effects secondary to the breakdown of T-cell mediated immune surveillance creates a dire need for intravesical alternatives to injectable antibodies like Nivolumab. Hence, we will use the overexpression of PD-L1 by orthotropic tumor provoked by carcinogen, N-butyl-N-4-hydroxybutyl nitrosamine (BBN) to demonstrate that molecular size is the key determinant for the permeation of instilled drugs and dyes into cancer foci. Accordingly, we hypothesize that intravesical contrast enhanced magnetic resonance imaging (MRI) after the instillation of Gadobutrol (0.8nm) mixed with Perfluorodecalin emulsion (>150nm) leverages the tumoritropic infiltration of Gadobutrol and the size-restricted diffusion of magnetically inert, Perfluorodecalin to enhance the image contrast of cancer foci for accomplishing virtual monitoring of tumor progression and tumor regression following intravesical immunotherapy of BMS-1166, a small molecule (640 Daltons), PD-1/PD-L1 inhibitor (IC50 of 1.4 nM). Our hypotheses will be tested in these interlocking Specific Aims: 1) To assess the criterion validity of intravesical contrast-enhanced MRI for monitoring BBN induced tumor progression. 2) To assess the discriminant validity of intravesical contrast-enhanced MRI for monitoring immunotherapy mediated BBN tumor regression. By ad libitum feeding of 0.05% BBN in water for up to 12 weeks, we will provoke tumor in immunocompetent 18-24 weeks old B6D2F1 mice for quantitative T1 relaxometry of normal and cancer foci and tumor vasculature at different time points to monitor BBN tumor progression, later confirmed by whole mount bladder histopathology and the expression of angiogenesis markers (Aim 1). To monitor the treatment mediated tumor regression (Aim 2), mice fed BBN for 10 weeks will be randomized to receive either a single 0.1mL instillation at 3mg/mL of Nivolumab or BCG or water-insoluble BMS-1166 entrapped in Sphingosomes or 50% DMSO followed by MRI, 6 weeks later to assess the effect of treatment on tumor size and the associated vasculature. Thus, we will enable MRI for imaging CIS, muscle invasion and tumor vasculature as well as develop a novel intravesical immunotherapeutic option.

该修订提案利用NCT 04369560的初步发现来开发膀胱内成像， 膀胱癌的免疫治疗方法（BCa）。而膀胱镜检查可发现外生性肿瘤（≥ 2 mm， 直径），可用成像模式的软组织分辨率差使得它们不足以检测 肿瘤侵袭、原位癌（CIS）和与侵袭性癌症相关的肿瘤脉管系统。这 肿瘤可视化的关键差距对高风险BCa患者的早期识别产生不利影响， 最有可能受益于化疗和/或免疫治疗的患者。虽然膀胱内免疫疗法 的卡介苗（BCG）阻止了BCa的进展和肌肉浸润，但仍有40%的患者表现出 BCG耐药肿瘤表达：程序性死亡（PD）L1，PDL 2与PD 1结合的配体 T细胞上的受体来抑制抗肿瘤反应。虽然抗肿瘤反应被抑制， 注射抗体，继发于T细胞介导的免疫监视破坏的不良反应 产生了对可注射抗体如纳武单抗的膀胱内替代品的迫切需求。因此，我们将使用 致癌物N-丁基-N-4-羟丁基亚硝胺引起的正交异性肿瘤中PD-L1的过度表达 (BBN)以证明分子大小是滴注药物和染料渗透的关键决定因素 转移到癌灶中因此，我们假设膀胱内造影增强磁共振成像 (MRI)滴入与全氟萘烷乳剂（> 150 nm）混合的钆布醇（0.8 nm）后， Gadobutrol的致瘤性浸润和磁惰性全氟萘烷的尺寸限制性扩散， 增强癌灶的图像对比度，实现肿瘤进展和肿瘤的虚拟监测 BMS-1166（一种小分子（640道尔顿）、PD-1/PD-L1）膀胱内免疫治疗后的消退 抑制剂（IC 50为1.4 nM）。我们的假设将在这些互锁的具体目标进行测试：1）评估 膀胱内对比增强MRI用于监测BBN诱导的肿瘤进展的标准有效性。2)到 评估膀胱内对比增强MRI监测免疫治疗介导的鉴别有效性 BBN肿瘤消退。通过自由采食0.05% BBN水溶液长达12周，我们将诱发肿瘤 在免疫活性的18-24周龄B6 D2 F1小鼠中进行正常和癌灶的定量T1弛豫测定 和肿瘤血管系统，以监测BBN肿瘤进展，随后通过整体 膀胱组织病理学及血管生成标志物的表达（目的1）。来监控治疗过程 为了使BBN介导的肿瘤消退（目标2），喂食BBN 10周的小鼠将随机接受单次BBN治疗。 以3 mg/mL的Nivolumab或BCG或包埋在鞘氨醇体中的水不溶性BMS-1166的0.1mL滴注 或50%DMSO，然后进行MRI，6周后评估治疗对肿瘤大小的影响和治疗后的肿瘤体积。 相关的脉管系统。因此，我们将使MRI成像CIS，肌肉浸润和肿瘤血管， 并开发一种新的膀胱内免疫选择。